Multiple rare inherited variants in a four generation schizophrenia family offer leads for complex mode of disease inheritance

John, Jibin; Bhattacharyya, Upasana; Yadav, Navneesh; Kukshal, Prachi; Bhatia, Triptish; Nimgaonkar, Vishwajit L.; Deshpande, Smita N.; Thelma, B.K.

doi:10.1016/j.schres.2019.11.041

Cited by 11 publications

(9 citation statements)

References 78 publications

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“…None of them was shared across different families [43]. John and colleagues recently reported five rare damaging mutations from five different genes shared by four affected members in a four-generation SZ family [44]. Together, these studies indicate that interactions of multiple rare deleterious mutations are parts of the SZ and BD landscape.…”

Section: Discussionmentioning

confidence: 99%

Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder

Chen

Huang

Fang

2021

IJMS

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Rare mutations associated with schizophrenia (SZ) and bipolar disorder (BD) usually have high clinical penetrance; however, they are highly heterogeneous and personalized. Identifying rare mutations is instrumental in making the molecular diagnosis, understanding the pathogenesis, and providing genetic counseling for the affected individuals and families. We conducted whole-genome sequencing analysis in two multiplex families with the dominant inheritance of SZ and BD. We detected a G327E mutation of SCN9A and an A654V mutation of DPP4 cosegregating with SZ and BD in one three-generation multiplex family. We also identified three mutations cosegregating with SZ and BD in another two-generation multiplex family, including L711S of SCN9A, M4554I of ABCA13, and P159L of SYT14. These five missense mutations were rare and deleterious. Mutations of SCN9A have initially been reported to cause congenital insensitivity to pain and neuropathic pain syndromes. Further studies showed that rare mutations of SCN9A were associated with seizure and autism spectrum disorders. Our findings suggest that SZ and BD might also be part of the clinical phenotype spectra of SCN9A mutations. Our study also indicates the oligogenic involvement in SZ and BD and supports the multiple-hit model of SZ and BD.

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Section: Discussionmentioning

confidence: 99%

Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder

Chen

Huang

Fang

2021

IJMS

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“…An intronic SNP in the PDE1C gene was found to be associated with autism spectrum disorder (ASD; p value < 1.0E−04) in a GWAS meta-analysis of 7387 ASD cases and 8567 controls [ 28 ]. Inherited missense variants in PDE1B gene have also been identified in probands with ASD [ 29 ] and with schizophrenia (SCZ) [ 30 ]. The knockdown of Pde1b in the hippocampus enhances spatial and contextual memory [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

2021

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Phosphodiesterases (PDEs) are enzymes involved in the homeostasis of both cAMP and cGMP. They are members of a family of proteins that includes 11 subfamilies with different substrate specificities. Their main function is to catalyze the hydrolysis of cAMP, cGMP, or both. cAMP and cGMP are two key second messengers that modulate a wide array of intracellular processes and neurobehavioral functions, including memory and cognition. Even if these enzymes are present in all tissues, we focused on those PDEs that are expressed in the brain. We took into consideration genetic variants in patients affected by neurodevelopmental disorders, phenotypes of animal models, and pharmacological effects of PDE inhibitors, a class of drugs in rapid evolution and increasing application to brain disorders. Collectively, these data indicate the potential of PDE modulators to treat neurodevelopmental diseases characterized by learning and memory impairment, alteration of behaviors associated with depression, and deficits in social interaction. Indeed, clinical trials are in progress to treat patients with Alzheimer’s disease, schizophrenia, depression, and autism spectrum disorders. Among the most recent results, the application of some PDE inhibitors (PDE2A, PDE3, PDE4/4D, and PDE10A) to treat neurodevelopmental diseases, including autism spectrum disorders and intellectual disability, is a significant advance, since no specific therapies are available for these disorders that have a large prevalence. In addition, to highlight the role of several PDEs in normal and pathological neurodevelopment, we focused here on the deregulation of cAMP and/or cGMP in Down Syndrome, Fragile X Syndrome, Rett Syndrome, and intellectual disability associated with the CC2D1A gene.

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“…Only a few studies have been reported where exome sequencing identified rare variants with high penetrance segregating in multiplex SCZ families [ 19 , 20 , 27 , 64 , 65 ]. Remarkably, in most of these studies, glutamatergic dysfunction appears to be chiefly involved in SCZ.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, a new paradigm has blossomed quickly; that is, the use of exome/genome sequencing to identify rare and ultra-rare highly penetrant variants contributing to the genetic etiology of SCZ [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Most of the SCZ-associated mutations and genes have been reported in sporadic cases through case-control or via patient-parents trio analyses [ 22 , 23 , 27 , 28 ]. Large multiplex families segregating SCZ hold great potential of discovery for relatively rare variants of high penetrance but have been rarely studied.…”

Section: Introductionmentioning

confidence: 99%

Rare Pathogenic Variants in Genes Implicated in Glutamatergic Neurotransmission Pathway Segregate with Schizophrenia in Pakistani Families

Fatima

Abdullah

Farooq

et al. 2021

Genes

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Schizophrenia is a disabling neuropsychiatric disorder of adulthood onset with high heritability. Worldwide collaborations have identified an association of ~270 common loci, with small individual effects and hence weak clinical implications. The recent technological feasibility of exome sequencing enables the identification of rare variants of high penetrance that refine previous findings and improve risk assessment and prognosis. We recruited two multiplex Pakistani families, having 11 patients and 19 unaffected individuals in three generations. We performed genome-wide SNP genotyping, next-generation mate pairing and whole-exome sequencing of selected members to unveil genetic components. Candidate variants were screened in unrelated cohorts of 508 cases, 300 controls and fifteen families (with 51 affected and 47 unaffected individuals) of Pakistani origin. The structural impact of substituted residues was assessed through in silico modeling using iTASSER. In one family, we identified a rare novel microduplication (5q14.1_q14.2) encompassing critical genes involved in glutamate signaling, such as CMYA5, HOMER and RasGRF2. The second family segregates two ultra-rare, predicted pathogenic variants in the GRIN2A (NM_001134407.3: c.3505C>T, (p.R1169W) and in the NRG3 NM_001010848.4: c.1951G>A, (p.E651K). These genes encode for parts of AMPA and NMDA receptors of glutamatergic neurotransmission, respectively, and the variants are predicted to compromise protein function by destabilizing their structures. The variants were absent in the aforementioned cohorts. Our findings suggest that rare, highly penetrant variants of genes involved in glutamatergic neurotransmission are contributing to the etiology of schizophrenia in these families. It also highlights that genetic investigations of multiplex, multigenerational families could be a powerful approach to identify rare genetic variants involved in complex disorders.

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Multiple rare inherited variants in a four generation schizophrenia family offer leads for complex mode of disease inheritance

Cited by 11 publications

References 78 publications

Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder

Involvement of Rare Mutations of SCN9A, DPP4, ABCA13, and SYT14 in Schizophrenia and Bipolar Disorder

Role of phosphodiesterases in the pathophysiology of neurodevelopmental disorders

Rare Pathogenic Variants in Genes Implicated in Glutamatergic Neurotransmission Pathway Segregate with Schizophrenia in Pakistani Families

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